Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy
Authors: Jacqueline A. French, Roger J. Porter, Emilio Perucca, Martin J. Brodie, Michael A. Rogawski, Simon Pimstone, Ernesto Aycardi, Cynthia Harden, Jenny Qian, Constanza Luzon Rosenblut, Christopher Kenney, Gregory N. Beatch, Robert Armstrong, Ekrem Kutluay, Pavel Klein, Toufic Fakhoury, Kore Liow, Stephen Flitman, Victor Biton, Michael Sperling, David Kudrow, Mercedes Jacobson, Kamil Detyniecki, Fawad Ahmed Khan (Prev: Ramsay), Evan Fertig, Ahmad Saeed Ata, Dean Naritoku, Bassel Abou-Khalil, Sasha Alick, Sami Aboumatar, Stephanie Callow (Prev: Moseley), Shahram Izadyar (Prev: Beach), Robert Wechsler, Jerzy Szaflarski, Nathan Fountain, Imran Ali, George Li, Theresa Rodgers-Neame, Elizabeth Waterhouse, Selim Benbadis, Steve Chung, Maria Sam, Joanne Rogin, Eric Segal, Claude Steriade, Amir Arain, Richard Pellegrino, Kenneth Laxer, Mushtaque Chachar, Conrad Nievera, Max Benzaquen, David Gloss, Ahmed Sadek, Lixin Zhang, Wei Ma, Aashit Shah, James Valeriano, Heidi Henninger, Jeffrey Tsai (Prev: Miller), Brian Moseley, Ruben Kuzniecky, Jerry Shih, Gregory Cascino, Alberto Pinzon-Ardila, Elizabeth Gerard, Samiya Rashid, Utku Uysal, Samuel Destefano, William Tatum, Suparna Krishnaiengar (Prev: Bautista), Raymond Faught, Eric Geller, Rolando Ania, Baljeet Sethi, Barbara Phillips, Micaela Chatman, Eric Segal(Satellite), Andrew Lerman, Naoir Zaher, Ricardo Ayala, Michael Gelfand, David Lesch, David Vossler, Paul Lyons, Ruben Kuzniecky (Satellite), David Steiner, Martin del Campo, Jean-François Clement, Seyed Mirsattari, Mary Connolly, Craig Heath, Mark Richardson, Khalid Hamandi, Elizabeth Galizia, Kathleen White, Anthony Marson, Rhys Thomas, Bernhard Steinhoff, Christian Brandt, Holger Lerche, Rainer Surges, Christoph Kellinghaus, Gabriel Moeddel, Rebekka Lehmann, Felix Rosenow, Thomas Mayer, Andreas Schulze-Bonhage, Christian Tilz, Manuel Toledo, Vicente Villanueva, Juan Carlos Sanchez, Pedro Serrano-Castro, Rodrigo Rocamora, Rosa Ana Saiz-Diaz, Maria Centeno, Juan Rodriguez-Uranga, Jose Serratosa, Antonio Gil-Nagel (Prev: Aledo, Juan Luis Becerra, Javier López-González, Dulce Campos, Violeta Sanchez, Manuel Simon-Talero, Irene Garcia Morales, Rafael Toledano, Vitalie Lisnic, Sergii Kharchuk, Umberto Aguglia, Carlo Galimberti, Laura Canafoglia, Antonio Gambardella, Francesca Bisulli, Chiara Pizzanelli, Carlo Di Bonaventura, Roman Shakarishvili
Journal: JAMA Neurology (2023)

Importance Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics. Objective To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs). Design, Setting, and Participants This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe. Interventions Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose). Main Outcomes and Measures The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted. Results A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% ( P &amp;amp;lt; .001 vs placebo; IQR, −80.4% to −16.9%) for 25 mg, 46.4% ( P &amp;amp;lt; .001 vs placebo; IQR, −76.7% to −14.0%) for 20 mg, and 33.2% ( P = .04 vs placebo; IQR, −61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, −37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported. Conclusions and Relevance The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs. Trial Registration ClinicalTrials.gov Identifier: NCT03796962